Substituted 2-oxo-3-phenyl-5-carbonylaminomethyl-1, 3-oxazolines and their use as anticoagulant and antithrombotics

ABSTRACT

The invention relates to the field of blood coagulation, more particularly, to novel compounds of general formula (I), 
     
       
         
         
             
             
         
       
     
     to a method for producing said compounds and to their use as active ingredients in medicaments for the prevention and/or the treatment of diseases.

The present invention relates to the field of blood coagulation. Inparticular, the present invention relates to novel oxazolidinonederivatives, to processes for their preparation and to their use asactive compounds in medicaments.

Blood coagulation is a protective mechanism of the organism which helpsto “seal” defects in the wall of the blood vessels quickly and reliably.Thus, loss of blood can be avoided or kept to a minimum. Hemostasisafter injury of the blood vessels is effected mainly by the coagulationsystem in which an enzymatic cascade of complex reactions of plasmaproteins is triggered. Numerous blood coagulation factors are involvedin this process, each of which factors converts, on activation, therespectively next inactive precursor into its active form. At the end ofthe cascade comes the conversion of soluble fibrinogen into insolublefibrin, resulting in the formation of a blood clot. In bloodcoagulation, traditionally the intrinsic and the extrinsic system, whichend in a joint reaction path, are distinguished. Here factor Xa, whichis formed from the proenzyme factor X, plays a key role, since itconnects the two coagulation paths. The activated serine protease Xacleaves prothrombin to thrombin. The resulting thrombin, in turn,cleaves fibrinogen to fibrin, a fibrous/gelatinous coagulant. Inaddition, thrombin is a potent effector of platelet aggregation whichlikewise contributes significantly to hemostasis.

Maintenance of normal hemostasis—between bleeding and thrombosis—issubject to a complex regulatory mechanism. Uncontrolled activation ofthe coagulant system or defective inhibition of the activation processesmay cause formation of local thrombi or embolisms in vessels (arteries,veins, lymph vessels) or in heart cavities. This may lead to seriousdisorders, such as myocardial infarct, angina pectoris (includingunstable angina), reocclusions and restenoses after angioplasty oraortocoronary bypass, stroke, transitory ischemic attacks, peripheralarterial occlusive disorders, pulmonary embolisms or deep veinthromboses; hereinbelow, these disorders are collectively also referredto as thromboembolic disorders. In addition, in the case of consumptioncoagulopathy, hypercoaguability may—systemically—result in disseminatedintravascular coagulation.

These thromboembolic disorders are the most frequent cause of morbidityand mortality in most industrialized countries (Pschyrembel, KlinischesWörterbuch [Clinical Dictionary], 257^(th) edition, 1994, Walter deGruyter Verlag, page 199 ff., entry “Blutgerinnung” [Blood Coagulation];Römpp Lexikon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart,entry “Blutgerinnung”; Lubert Stryer, Biochemie [Biochemistry], Spektrumder Wissenschaft Verlagsgesellschaft mbH Heidelberg, 1990, page 259ff.).

The anticoagulants, i.e. substances for inhibiting or preventing bloodcoagulation, which are known from the prior art have various, oftengrave disadvantages. Accordingly, in practice, an efficient treatmentmethod or prophylaxis of thromboembolic disorders is very difficult andunsatisfactory.

In the therapy and prophylaxis of thromboembolic disorders, use isfirstly made of heparin, which is administered parenterally orsubcutaneously. Owing to more favorable pharmacokinetic properties,preference is nowadays more and more given to low-molecular-weightheparin; however, even with low-molecular-weight heparin, it is notpossible to avoid the known disadvantages described below, which areinvolved in heparin therapy. Thus, heparin is ineffective whenadministered orally and has a relatively short half-life. Since heparininhibits a plurality of factors of the blood coagulation cascade at thesame time, the action is nonselective. Moreover, there is a high risk ofbleeding; in particular, brain hemorrhages and gastrointestinal bleedingmay occur, which may result in thrombopenia, drug-induced alopecia orosteoporosis (Pschyrembel, Klinisches Wörterbuch, 257^(th) edition,1994, Walter de Gruyter Verlag, page 610, entry “Heparin”; Römpp LexikonChemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart, entry“Heparin”).

A second class of anticoagulants are the vitamin K antagonists. Theseinclude, for example, 1,3-indanediones, and especially compounds such aswarfarin, phenprocoumon, dicumarol and other coumarin derivatives whichinhibit the synthesis of various products of certain vitamin K-dependentcoagulation factors in the liver in a nonselective manner. Owing to themechanism of action, however, the onset of the action is very slow(latency to the onset of action 36 to 48 hours). It is possible toadminister the compounds orally; however, owing to the high risk ofbleeding and the narrow therapeutic index, a time-consuming individualadjustment and monitoring of the patient are required. Moreover, otheradverse effects, such as gastrointestinal disturbances, hair loss andskin necroses, have been described (Pschyrembel, Klinisches Wörterbuch,257^(th) edition, 1994, Walter de Gruyter Verlag, page 292 ff., entry“coumarin derivatives”; Ullmann's Encyclopedia of Industrial Chemistry,5^(th) edition, VCH Verlagsgesellschaft, Weinheim, 1985-1996, entry“vitamin K”).

Recently, a novel therapeutic approach for the treatment and prophylaxisof thromboembolic disorders has been described. This novel therapeuticapproach aims to inhibit factor Xa (cf. WO-A-99/37304; WO-A-99/06371; J.Hauptmann, J. Stürzebecher, Thrombosis Research 1999, 93, 203; F.Al-Obeidi, J. A. Ostrem, Factor Xa inhibitors by classical andcombinatorial chemistry, DDT 1998, 3, 223; F. Al-Obeidi, J. A. Ostrem,Factor Xa inhibitors, Exp. Opin. Ther. Patents 1999, 9, 931; B. Kaiser,Thrombin and factor Xa inhibitors, Drugs of the Future 1998, 23, 423; A.Uzan, Antithrombotic agents, Emerging Drugs 1998, 3, 189; B.-Y. Zhu, R.M. Scarborough, Curr. Opin. Card. Pulm. Ren. Inv. Drugs 1999, 1 (1),63). It has been shown that, in animal models, various both peptidic andnonpeptidic compounds are effective as factor Xa inhibitors.

Accordingly, it is an object of the present invention to provide novelsubstances for controlling disorders, which substances have a widetherapeutic spectrum.

In particular, they should be suitable for a more efficient prophylaxisand/or treatment of thromboembolic disorders, avoiding—at least to someextent—the disadvantages of the prior art described above, where theterm “thromboembolic disorders” in the context of the present inventionis to be understood as meaning, in particular, serious disorders, suchas myocardial infarct, angina pectoris (including unstable angina),reocclusions and restenoses after angioplasty or aortocoronary bypass,stroke, transitory ischemic attacks, peripheral arterial occlusivedisorders, pulmonary embolisms or deep venous thromboses.

It is another object of the present invention to provide novelanticoagulants which inhibit the blood coagulation factor Xa withincreased selectivity, avoiding—at least to some extent—the problems ofthe therapeutic methods for thromboembolic disorders known from theprior art.

The present invention provides compounds of the formula (I),

in which

-   R¹ represents (C₆-C₁₄)-aryl, 5- to 10-membered heteroaryl having up    to three heteroatoms from the group consisting of N, O and S or 5-    to 10-membered heterocyclyl having up to three heteroatoms from the    group consisting of N, O and S, where the rings may be mono- to    trisubstituted, independently of one another, by halogen,    (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl,    (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl,    trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, oxo,    carboxyl or cyano,-   R² represents a radical —C(O)NR⁸R⁹, —N(R¹⁰)C(O)R¹¹ or

-   -   where    -   R⁸ represents hydrogen,        -   (C₁-C₆)-alkyl which for its part may be substituted by            halogen, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl,            oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano,        -   (C₆-C₁₄)-aryl which for its part may be substituted by            halogen, (C₁-C₆)-alkyl, amino, mono- or            di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy,            (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl,            trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or            cyano,        -   or (C₃-C₇)-cycloalkyl,        -   and    -   R⁹ represents (C₁-C₆)-alkyl which for its part may be        substituted by halogen, amino, mono- or di-(C₁-C₆)-alkylamino,        hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano,        -   (C₆-C₁₄)-aryl which for its part may be substituted by            halogen, (C₁-C₆)-alkyl, amino, mono- or            di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy,            (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl,            trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or            cyano,        -   or (C₃-C₇)-cycloalkyl,    -   or    -   R⁸ and R⁹ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle which may contain        up to two further heteroatoms from the group consisting of N, O        and S and which may furthermore be mono- to trisubstituted,        independently of one another, by halogen, (C₁-C₆)-alkyl, amino,        mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy,        trifluoromethyl or cyano,    -   R¹⁰ and R¹¹, independently of one another, represent        (C₁-C₆)-alkyl which for its part may be substituted by halogen,        amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo,        (C₁-C₆)-alkoxy, trifluoromethyl or cyano, (C₆-C₁₄)-aryl which        for its part may be substituted by halogen, (C₁-C₆)-alkyl,        amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy,        (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl,        trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano,        -   or (C₃-C₇)-cycloalkyl,    -   or    -   R¹⁰ and R¹¹ together with the N—C(O) group to which they are        attached form a 4- to 7-membered heterocycle which may contain        up to two further heteroatoms from the group consisting of N, O        and S and which may furthermore be mono- to trisubstituted,        independently of one another, by halogen, (C₁-C₆)-alkyl, amino,        mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy,        trifluoromethyl or cyano,    -   x represents 0 or 1,    -   R¹² and R¹³ together with the nitrogen atom to which they are        attached form a 4- to 6-membered heterocycle which may contain a        further heteroatom from the group consisting of N, O and S and        which may be up to disubstituted, independently of one another,        by amino, hydroxyl, halogen, trifluoromethyl, cyano, oxo, mono-        or di-(C₁-C₄)-alkylamino, (C₁-C₄)-alkoxy, carboxamido,        (C₁-C₄)-alkylcarbonyl or (C₃-C₅)-cycloalkylcarbonyl,

-   R³, R⁴, R⁵ and R⁶, independently of one another, represent hydrogen,    halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, mono-    or di-(C₁-C₆)-alkylaminocarbonyl, hydroxyl, (C₁-C₆)-alkoxy,    (C₁-C₆)-alkanoyl, (C₁-C₆)-alkanoylamino, trifluoromethyl, carbamoyl,    nitro or cyano,    and

-   R⁷ represents hydrogen or (C₁-C₆)-alkyl,    and their salts, hydrates, hydrates of the salts and solvates,    but excluding compounds of the general formula (I) in which the    radical R¹ is an optionally substituted thiophene radical.

To date, oxazolidinones have essentially only been described asantibiotics, and in individual cases also as MAO inhibitors andfibrinogen antagonists (review: Riedl, B., Endermann, R., Exp. Opin.Ther. Patents 1999, 9 (5), 625), where a small 5-[acylaminomethyl] group(preferably 5-[acetylaminomethyl]) appears to be essential for theantibacterial activity.

Substituted aryl- and heteroarylphenyloxazolidinones in which a mono- orpolysubstituted phenyl radical may be attached to the N atom of theoxazolidinone ring and which may have an unsubstitutedN-methyl-2-thiophenecarboxamide radical in the 5-position of theoxazolidinone ring, and their use as antibacterial substances, are knownfrom U.S. Pat. No. 5,929,248, U.S. Pat. No. 5,801,246, U.S. Pat. No.5,756,732, U.S. Pat. No. 5,654,435, U.S. Pat. No. 5,654,428 and U.S.Pat. No. 5,565,571.

In addition, benzamidine-containing oxazolidinones are known assynthetic intermediates in the synthesis of factor Xa inhibitors and/orfibrinogen antagonists (WO-A-99/31092, EP-A-623615).

Depending on the substitution pattern, the compounds of the generalformula (I) according to the invention may exist in stereoisomeric formswhich are either like image and mirror image (enantiomers) or not likeimage and mirror image (diastereomers). The invention relates both tothe enantiomers or diastereomers and to their respective mixtures. Theracemic forms, like the diastereomers, can be separated in a knownmanner into the stereoisomerically uniform components.

Furthermore, certain compounds of the general formula (I) can be presentin tautomeric forms. This is known to the person skilled in the art, andsuch compounds are likewise within the scope of the invention.

Salts of the compounds according to the invention are physiologicallyacceptable salts of the compounds according to the invention withinorganic or organic acids. Preference is given to salts with inorganicacids, such as, for example, hydrochloric acid, hydrobromic acid,phosphoric acid or sulfuric acid, or to salts with organic carboxylic orsulfonic acids, such as, for example, acetic acid, trifluoroacetic acid,propionic acid, maleic acid, fumaric acid, malic acid, citric acid,tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid ornaphthalenedisulfonic acid.

Salts may also be physiologically acceptable salts with customary bases,such as, for example, alkali metal salts (for example sodium orpotassium salts), alkaline earth metal salts (for example calcium ormagnesium salts) or ammonium salts, derived from ammonia or organicamines, such as, for example, diethylamine, triethylamine,ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine,dihydroabietyl-amine or methylpiperidine.

Moreover, the invention also embraces prodrugs of the compoundsaccording to the invention. According to the invention, prodrugs arethose forms of the compounds of the formula (I) which for their part maybe biologically active or inactive, but which can be converted into thecorresponding biologically active form (for example metabolically orsolvolytically) under physiological conditions.

According to the invention, “hydrates” or “solvates” are forms of thecompounds of the general formula (I) which form a molecule compound or acomplex in the solid or liquid state by hydration with water orcoordination with solvent molecules. Examples of hydrates aresesquihydrates, monohydrates, dihydrates or trihydrates. Equallysuitable are the hydrates or solvates of salts of the compoundsaccording to the invention.

Halogen represents fluorine, chlorine, bromine and iodine. Preference isgiven to chlorine, bromine or fluorine.

(C₁-C₆)-Alkyl represents a straight-chain or branched alkyl radicalhaving 1 to 6 carbon atoms. Examples which may be mentioned are: methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl andn-hexyl. The corresponding alkyl groups with fewer carbon atoms, suchas, for example, (C₁-C₄)-alkyl, are derived analogously from thisdefinition. In general, preference is given to (C₁-C₄)-alkyl.

The meaning of the corresponding component of other more complexsubstituents, such as, for example, in the case of mono- or dialkylaminoor mono- or dialkylaminocarbonyl, is likewise derived from thisdefinition.

(C₃-C₇)-Cycloalkyl represents a cyclic alkyl radical having 3 to 7carbon atoms. Examples which may be mentioned are: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Preference is givento cyclopropyl, cyclopentyl and cyclohexyl.

(C₁-C₆)-Alkoxy represents a straight-chain or branched alkoxy radicalhaving 1 to 6 carbon atoms. Examples which may be mentioned are:methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentoxy and n-hexoxy. The corresponding alkoxy groupshaving fewer carbon atoms, such as, for example, (C₁-C₄)-alkoxy, arederived analogously from this definition. In general, preference isgiven to (C₁-C₄)-alkoxy.

(C₁-C₆)-Alkanoyl represents a straight-chain or branched alkyl radicalhaving 1 to 6 carbon atoms which carries a doubly attached oxygen atomin the 1-position and is attached via the 1-position. Examples which maybe mentioned are: formyl, acetyl, propionyl, n-butyryl, i-butyryl,pivaloyl, n-hexanoyl. The corresponding alkanoyl groups with fewercarbon atoms, such as, for example, (C₁-C₅)-alkanoyl, (C₁-C₄)-alkanoyland (C₁-C₃)-alkanoyl, are derived analogously from this definition. Ingeneral, preference is given to (C₁-C₃)-alkanoyl.

The meaning of the corresponding component of other more complexsubstituents, such as, for example, alkanoylamino, is likewise derivedfrom this definition.

(C₆-C₁₄)-Aryl represents an aromatic radical having 6 to 14 carbonatoms. Examples which may be mentioned are: phenyl, naphthyl,phenanthrenyl and anthracenyl. The corresponding aryl groups with fewercarbon atoms, such as, for example, (C₆-C₁₀)-aryl are derivedanalogously from this definition. In general, preference is given to(C₆-C₁₀)-aryl.

5- to 10-membered heteroaryl having up to 3 heteroatoms from the groupconsisting of N, O and S represents a mono- or bicyclic, optionallybenzofused heteroaromatic which is attached via a carbon ring atom or,via a nitrogen ring atom of the heteroaromatic. Examples which may bementioned are: pyridyl, pyridyl N-oxide, pyrimidyl, pyridazinyl,pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl or isoxazolyl, indolinyl, indolyl, benzo[b]thienyl,benzo[b]furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl,quinazolinyl. The corresponding heteroaromatics having a smaller ringsize, such as, for example, 5- to 8-membered heteroaryl, are derivedanalogously from this definition. In general, preference is given to 5-or 6-membered aromatic heterocycles, such as, for example, pyridyl,pyridyl N-oxide, pyrimidyl, pyridazinyl, furyl and thienyl.

5- to 10-membered heterocyclyl having up to 3 heteroatoms from the groupconsisting of S, N and O represents a saturated or partially unsaturatedmono- or bicyclic, optionally benzofused heterocycle which is attachedvia a carbon ring atom or a nitrogen ring atom. Examples which may bementioned are: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl,morpholinyl N-oxide, thiomorpholinyl, azepinyl and 1,4-diazepinyl.Preference is given to piperidinyl, morpholinyl, thiomorpholinyl andpyrrolidinyl.

The corresponding heterocycles having a smaller ring size, such as, forexample, 4- to 8-membered heterocycles, are derived analogously fromthis definition.

Preference is given to compounds of the formula (I),

in which

-   R¹ represents (C₆-C₁₄)-aryl, 5- to 10-membered heteroaryl having one    nitrogen or oxygen atom as heteroatom and optionally up to two    further heteroatoms from the group consisting of N, O and S or 5- to    10-membered heterocyclyl having up to three heteroatoms from the    group consisting of N, O and S, where the rings may be mono- to    trisubstituted, independently of one another, by halogen,    (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl,    (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl,    trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, oxo,    carboxyl or cyano,-   R² represents a radical —C(O)NR⁸R⁹, —N(R¹⁰)C(O)R¹¹ or

-   -   where    -   R⁸ represents hydrogen,        -   (C₁-C₆)-alkyl which for its part may be substituted by            halogen, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl,            oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano,        -   (C₆-C₁₄)-aryl which for its part may be substituted by            halogen, (C₁-C₆)-alkyl, amino, mono- or            di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy,            (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl,            trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or            cyano,        -   or (C₃-C₇)-cycloalkyl,        -   and    -   R⁹ represents (C₁-C₆)-alkyl which for its part may be        substituted by halogen, amino, mono- or di-(C₁-C₆)-alkylamino,        hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano,        -   (C₆-C₁₄)-aryl which for its part may be substituted by            halogen, (C₁-C₆)-alkyl, amino, mono- or            di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy,            (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl,            trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or            cyano,        -   or (C₃-C₇)-cycloalkyl,    -   or    -   R⁸ and R⁹ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle which may contain        up to two further heteroatoms from the group consisting of N, O        and S and which may furthermore be mono- to trisubstituted,        independently of one another, by halogen, (C₁-C₆)-alkyl, amino,        mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy,        trifluoromethyl or cyano,    -   R¹⁰ and R¹¹, independently of one another, represent        (C₁-C₆)-alkyl which for its part may be substituted by halogen,        amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo,        (C₁-C₆)-alkoxy, trifluoromethyl or cyano, (C₆-C₁₄)-aryl which        for its part may be substituted by halogen, (C₁-C₆)-alkyl,        amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy,        (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl,        trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano,        -   or (C₃-C₇)-cycloalkyl,    -   or    -   R¹⁰ and R¹¹ together with the N—C(O) group to which they are        attached form a 4- to 7-membered heterocycle which may contain        up to two further heteroatoms from the group consisting of N, O        and S and which may furthermore be mono- to trisubstituted,        independently of one another, by halogen, (C₁-C₆)-alkyl, amino,        mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy,        trifluoromethyl or cyano,    -   x represents 0 or 1,    -   R¹² and R¹³ together with the nitrogen atom to which they are        attached form a 4- to 6-membered heterocycle which may contain a        further heteroatom from the group consisting of N, O and S and        which may be up to disubstituted, independently of one another,        by amino, hydroxyl, halogen, trifluoromethyl, cyano, oxo, mono-        or di-(C₁-C₄)-alkylamino, (C₁-C₄)-alkoxy, carboxamido,        (C₁-C₄)-alkylcarbonyl or (C₃-C₅)-cycloalkylcarbonyl,

-   R³, R⁴, R⁵ and R⁶, independently of one another, represent hydrogen,    halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, mono-    or di-(C₁-C₆)-alkylaminocarbonyl, hydroxyl, (C₁-C₆)-alkoxy,    (C₁-C₆)-alkanoyl, (C₁-C₆)-alkanoylamino, trifluoromethyl, carbamoyl,    nitro or cyano,    and

-   R⁷ represents hydrogen or (C₁-C₆)-alkyl,    and their salts, hydrates, hydrates of the salts and solvates.

Particular preference is given to compounds of the formula (I),

in which

-   R¹ represents phenyl, naphthyl, 5- to 8-membered heteroaryl having    one nitrogen or oxygen atom as heteroatom and optionally up to two    further heteroatoms from the group consisting of N, O and S or 5- to    8-membered heterocyclyl having up to three heteroatoms from the    group consisting of N, O and S, where the rings may be mono- to    trisubstituted, independently of one another, by halogen,    (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, cyano, trifluoromethyl,    trifluoromethoxy or trifluoromethylthio,-   R² represents a radical —C(O)NR⁸R⁹, —N(R¹⁰)C(O)R¹¹ or

-   -   where    -   R⁸ represents hydrogen, (C₁-C₄)-alkyl which for its part may be        substituted by halogen, amino, mono- or di-(C₁-C₄)-alkylamino,        hydroxyl, oxo, (C₁-C₄)-alkoxy, trifluoromethyl or cyano or        (C₃-C₇)-cycloalkyl,        -   and    -   R⁹ represents (C₁-C₄)-alkyl which for its part may be        substituted by halogen, amino, mono- or di-(C₁-C₄)-alkylamino,        hydroxyl, oxo, (C₁-C₄)-alkoxy, trifluoromethyl or cyano, or        (C₃-C₇)-cycloalkyl,    -   or    -   R⁸ and R⁹ together with the nitrogen atom to which they are        attached form a 4- to 7-membered heterocycle which may contain        up to two further heteroatoms from the group consisting of N, O        and S and which may furthermore be mono- to trisubstituted,        independently of one another, by halogen, (C₁-C₆)-alkyl, amino,        mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy,        trifluoromethyl or cyano,    -   R¹⁰ and R¹¹, independently of one another, represent        (C₁-C₆)-alkyl which for its part may be substituted by halogen,        amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo,        (C₁-C₆)-alkoxy, trifluoromethyl or cyano, or (C₃-C₇)-cycloalkyl,    -   or    -   R¹⁰ and R¹¹ together with the N—C(O) group to which they are        attached form a 4- to 7-membered heterocycle which may contain        up to two further heteroatoms from the group consisting of N, O        and S and which may furthermore be mono- to trisubstituted,        independently of one another, by halogen, (C₁-C₆)-alkyl, amino,        mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy,        trifluoromethyl or cyano,    -   x represents 0 or 1,    -   R¹² and R¹³ together with the nitrogen atom to which they are        attached form a 4- to 6-membered heterocycle which may contain a        further heteroatom from the group consisting of N, O and S and        which may be monosubstituted by amino, hydroxyl, halogen,        trifluoromethyl, cyano, oxo, mono- or di-(C₁-C₄)-alkylamino,        (C₁-C₄)-alkoxy, carboxamido, (C₁-C₄)-alkylcarbonyl or        (C₃-C₅)-cycloalkylcarbonyl,

-   R³ and R⁶, independently of one another, represent hydrogen,    halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino,    hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkanoylamino, cyano,    trifluoromethyl or nitro,

-   R⁴ and R⁵ represent hydrogen,    and

-   R⁷ represents hydrogen or (C₁-C₄)-alkyl,    and their salts, hydrates, hydrates of the salts and solvates.

Very particular preference is given to compounds of the formula (I),

in which

-   R¹ represents phenyl, furyl, dihydrothienyl, thiazolyl, pyrrolyl or    pyridyl, where the rings may be mono- to trisubstituted,    independently of one another, by fluorine, chlorine, bromine,    (C₁-C₄)-alkyl, trifluoromethyl, trifluoromethoxy or    trifluoromethylthio,-   R² represents a radical —C(O)NR⁸R⁹, —N(R¹⁰)C(O)R¹¹ or

-   -   where    -   R⁸ and R⁹, independently of one another, represent (C₁-C₄)-alkyl        which for its part may be substituted by halogen, amino, mono-        or di-(C₁-C₄)-alkylamino, hydroxyl, oxo, (C₁-C₄)-alkoxy,        trifluoromethyl or cyano, or (C₃-C₇)-cycloalkyl,    -   or    -   R⁸ and R⁹ together with the nitrogen atom to which they are        attached represent morpholinyl, pyrrolidinyl, thiomorpholinyl or        piperidinyl, where the rings may be mono- or disubstituted by        (C₁-C₄)-alkyl and/or oxo,    -   R¹⁰ and R¹¹, independently of one another, represent        (C₁-C₆)-alkyl which for its part may be substituted by halogen,        amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo,        (C₁-C₆)-alkoxy, trifluoromethyl or cyano, or (C₃-C₇)-cycloalkyl,    -   or    -   R¹⁰ and R¹¹ together with the N—C(O) group to which they are        attached represent morpholinonyl, pyrrolidinonyl,        thiomorpholinonyl or piperidinonyl, where the rings may be mono-        or disubstituted by (C₁-C₄)-alkyl,    -   x represents 0 or 1,    -   R¹² and R¹³ together with the nitrogen atom to which they are        attached form a 5- or 6-membered saturated heterocycle which may        contain a further oxygen atom in the ring and which may be        monosubstituted by amino or hydroxyl,    -   R³ represents hydrogen, fluorine, chlorine, bromine,        (C₁-C₄)-alkyl, amino, mono- or di-(C₁-C₃)-alkylamino, cyano or        nitro,

-   R⁴, R⁵ and R⁶ represent hydrogen,    and

-   R⁷ represents hydrogen,    and their salts, hydrates, hydrates of the salts and solvates.

The present invention also provides a process for preparing thecompounds of the general formula (I) according to the invention where

compounds of the formula (II)

in which R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined aboveare reacted with carboxylic acids of the formula (III)

in which R¹ is as defined above,or else with the corresponding carbonyl halides, preferably carbonylchlorides, or else with the corresponding symmetric or mixed carboxylicanhydrides of the carboxylic acids of the formula (III) defined abovein inert solvents, if appropriate in the presence of auxiliaries and/orbases, to give compounds of the formula (I).

Solvents suitable for the process described above are organic solventswhich are inert under the reaction conditions. These include halogenatedhydrocarbons, such as dichloromethane, trichloromethane, carbontetrachloride or 1,2-dichloroethane, ethers, such as diethyl ether,dioxane or tetrahydrofuran, or other solvents, such as ethyl acetate,dimethylformamide, acetonitrile, pyridine, N-methylpyrrolidone (NMP) ordimethylacetamide.

It is also possible to use solvent mixtures of the solvents mentionedabove.

Suitable for use as auxiliaries for the formation of the amide arecustomary condensing agents and/or activating agents, such ascarbodiimides, for exampleN'-(3-dimethylaminopropyl)-N-ethylcarbodiimide.HCl (EDC),N,N′-dicyclohexylcarbodiimide (DCC), if appropriate in the presence of1-hydroxy-1H-benzotriazole.H₂O(HOBt),benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate(PyBOP®), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TBTU),2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), or carbonyl compounds, such ascarbonyldiimidazole.

Suitable for use as bases are trialkylamines, for example triethylamine,N-methylmorpholine (NMM), N-methylpiperidine, diisopropylethylamine(Hünig base) or 4-N,N-dimethylaminopyridine (DMAP) or pyridine.

The reactions are generally carried out in a temperature range of from0° C. to the reflux temperature, preferably in the range of from 0° C.to room temperature.

The reactions can be carried out under atmospheric, elevated or reducedpressure (for example in the range of from 0.5 to 5 bar). In general,the reactions are carried out under atmospheric pressure.

The compounds of the general formulae (II) and (1H) are known per se tothe person skilled in the art or can be prepared by customary methods.For oxazolidinones, in particular the 5-(aminomethyl)-2-oxooxazolidinesrequired, cf. WO-A-98/01446; WO-A-93/23384; WO-A-97/03072; J. A. Tuckeret al., J. Med. Chem. 1998, 41, 3727; S. J. Brickner et al., J. Med.Chem. 1996, 39, 673; W. A. Gregory et al., J. Med. Chem. 1989, 32, 1673.

The compounds of the general formula (I) according to the invention havean unforeseeable useful pharmacological activity spectrum and aretherefore particularly suitable for the prophylaxis and/or treatment ofdisorders.

The compounds of the general formula (I) according to the invention actin particular as anticoagulants and can therefore preferably be employedin medicaments for the prophylaxis and/or therapy of thromboembolicdisorders. For the purpose of the present invention, “thromboembolicdisorders” include, in particular, serious disorders such as myocardialinfarct, angina pectoris (including unstable angina), reocclusions andrestenoses after angioplasty or aortocoronary bypass, stroke, transitoryischemic attacks, peripheral arterial occlusion disorders, pulmonaryembolisms or deep vein thromboses.

Furthermore, the compounds of the general formula (I) according to theinvention are also suitable for treating disseminated intravascularcoagulation (DIC).

Finally, the compounds of the general formula (I) according to theinvention are also suitable for the prophylaxis and/or treatment ofatherosclerosis and arthritis, and additionally also for the prophylaxisand/or treatment of Alzheimer's disease and cancer.

Furthermore, the present invention also includes a method for preventingblood coagulation in vitro, in particular in banked blood or biologicalsamples which contain factor Xa, which method is characterized in thatcompounds of the general formula (I) are added.

The compounds of the general formula (I) according to the invention actin particular as selective inhibitors of the blood coagulation factor Xaand do not inhibit, or only inhibit at considerably higherconcentrations, other serine proteases as well, such as thrombin,plasmin or trypsin.

In the context of the present invention, inhibitors of the bloodcoagulation factor Xa in which the IC₅₀ values for the factor Xainhibition are lower by a factor of 100, preferably by a factor of 500,in particular by a factor of 1000, than the IC₅₀ values for theinhibition of other serine proteases, in particular thrombin, plasminand trypsin, are referred to as being “selective”, where with a view tothe test methods for selectivity, reference is made to the test methodsof Examples A-1) a.1) and a.2) described below.

All customary administration forms are suitable for administration ofthe compounds according to the invention. Administration is preferablycarried out orally, lingually, sublingually, buccally, rectally orparenterally (i.e. bypassing the intestinal tract, that isintravenously, intraarterially, intracardially, intracutaneously,subcutaneously, transdermally, intraperitoneally or intramuscularly).Particularly suitable are oral and intravenous administration. Veryparticular preference is given to oral administration, this being afurther advantage with respect to the prior-art therapy ofthromboembolic disorders.

The novel active compounds of the general formula (I) can be convertedin a known manner into the customary formulations, such as tablets,sugar-coated tablets, pills, granules, aerosols, syrups, emulsions,suspensions and solutions, using inert non-toxic pharmaceuticallysuitable excipients or solvents. Here, the therapeutically activecompound should in each case be present in a concentration of from about0.1 to 95% by weight, preferably from 0.5 to 90% by weight, inparticular from 1 to 85% by weight, of the total mixture, i.e. inamounts which are sufficient in order to achieve the dosage rangeindicated.

In spite of this, if appropriate, it may be necessary to depart from theamounts mentioned, namely depending on the body weight or on the type ofadministration route, on the individual response to the medicament, onthe manner of its formulation and the time or interval at whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the abovementioned minimum amount, while in othercases the upper limit mentioned must be exceeded. In the case of theadministration of relatively large amounts, it may be advisable todivide these into several individual administrations over the course ofthe day.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, it being possible, for example if thediluent used is water, optionally to use organic solvents as auxiliarysolvents.

In general it has proved advantageous in the case of intravenousadministration to administer amounts from approximately 0.001 to 10mg/kg, preferably approximately 0.01 to 10 mg/kg, in particularapproximately 0.1 to 8 mg/kg, of body weight to achieve effectiveresults.

In general, it has proved advantageous in the case of oraladministration to administer amounts from approximately 0.01 to 50mg/kg, preferably approximately 0.1 to 10 mg/kg, in particularapproximately 0.5 to 8 mg/kg, of body weight to achieve effectiveresults.

In spite of this, if appropriate, it may be necessary in the case ofintravenous or oral administration to depart from the amounts mentioned,namely depending on the body weight or on the type of administrationroute, on the individual response to the medicament, on the manner ofits formulation and the time or interval at which administration takesplace. Thus, in some cases it may be adequate to manage with less thanthe abovementioned minimum amount, while in other cases the upper limitmentioned must be exceeded. In the case of the administration ofrelatively large amounts, it may be advisable to divide these over thecourse of the day, namely into several individual doses or as acontinuous infusion.

Compared to the conventional preparations for treating thromboembolicdisorders, the compounds of the general formula (I) according to theinvention are distinguished in particular by the fact that a greatertherapeutic range is achieved by the selective inhibition of factor Xa.For the patient, this means a lower risk of bleeding, and for thetreating physician, this means that the patient is easier to adjust.Moreover—owing to the mechanism—the onset of action is more rapid. Aboveall, however, the compounds according to the invention permit an oraladministration form, which is a further advantage of the therapy withthe compounds according to the invention.

The present invention is illustrated by the examples below.

A EVALUATION OF THE PHYSIOLOGICAL ACTIVITY 1. General Test Methods

The particularly advantageous biological properties of the compoundsaccording to the invention can be determined by the following methods.

a) Test Description (In Vitro) a.1) Determination of the Factor XaInhibition

The enzymatic activity of human factor Xa (FXa) was measured using theconversion of a chromogenic substrate specific for FXa. Factor Xacleaves p-nitroaniline from the chromogenic substrate. Thedeterminations were carried out in microtiter plates as follows.

The test substances, in various concentrations, were dissolved in DMSOand incubated at 25° C. with human FXa (0.5 nmol/l dissolved in 50mmol/l of tris buffer [C,C,C-tris(hydroxymethyl)aminomethane], 150mmol/l of NaCl, 0.1% BSA (bovine serum albumin), pH=8.3) for 10 minutes.Pure DMSO was used as control. The chromogenic substrate (150 μmol/l ofPefachrome® FXa from Pentapharm) was then added. After an incubationtime of 20 minutes at 25° C., the extinction at 405 nm was determined.The extinctions of the test mixtures containing test substance werecompared with the control mixtures without test substance, and the IC₅₀values were calculated from these data.

Example IC₅₀ 1 20 nM 6 26 nM

a.2) Determination of the Selectivity

To assess selective FXa inhibition, the test substances were examinedfor their inhibition of other human serine proteases such as thrombin,trypsin and plasmin. To determine the enzymatic activity of thrombin (75mU/ml), trypsin (500 mU/ml) and plasmin (3.2 nmol/l), these enzymes weredissolved in tris buffer (100 mmol/l, 20 mmol/l CaCl₂, pH=8.0) andincubated with test substance or solvent for 10 minutes. The enzymaticreaction was then started by adding the corresponding specificchromogenic substrates (Chromozym Thrombin® from Boehringer Mannheim,Chromozym Trypsin® from Boehringer Mannheim, Chromozym Plasmin® fromBoehringer Mannheim) and the extinction at 405 nm was determined after20 minutes. All determinations were carried out at 37° C. Theextinctions of the test mixtures containing test substance were comparedwith the control samples without test substance, and the IC₅₀ valueswere calculated from these data.

a.3) Determination of the Anticoagulant Action

The anticoagulant action of the test substances was determined in vitroin human plasma. To this end, human blood was drawn off in a mixingratio of sodium citrate/blood of 1/9 using a 0.11 molar sodium citratesolution as receiver. Immediately after the blood had been drawn off, itwas mixed thoroughly and centrifuged at about 2000 g for 10 minutes. Thesupernatant was pipetted off. The prothrombin time (PT, synonyms:thromboplastin time, quick test) was determined in the presence ofvarying concentrations of test substance or the corresponding solventusing a commercial test kit (Neoplastin® from Boehringer Mannheim). Thetest compounds were incubated with the plasma at 37° C. for 10 minutes.Coagulation was then started by addition of thromboplastin, and the timewhen coagulation occurred was determined. The concentration of testsubstance which effected a doubling of the prothrombin time wasdetermined.

b) Determination of the Antithrombotic Activity (In Vivo) b.1)Arteriovenous Shunt Model (Rat)

Fasting male rats (strain: HSD CPB:WU) having a weight of 200-250 g wereanesthetized using a Rompun/Ketavet solution (12 mg/kg/50 mg/kg).Thrombus formation was initiated in an arteriovenous shunt in accordancewith the method described by Christopher N. Berry et al., Br. J.Pharmacol. (1994), 113, 1209-1214. To this end, the left jugular veinand the right carotid artery were exposed. The two vessels wereconnected by an extracorporeal shunt using a polyethylene tube (PE 60)of a length of 10 cm. In the middle, this polyethylene tube was attachedto a further polyethylene tube (PE 160) of a length of 3 cm whichcontained a roughened nylon thread which had been arranged to form aloop, to form a thrombogenic surface. The extracorporeal circulation wasmaintained for 15 minutes. The shunt was then removed and the nylonthread with the thrombus was weighed immediately. The weight of thenylon thread on its own had been determined before the experiment wasstarted. Before the extracorporeal circulation was set up, the testsubstances were administered to the animals while awake eitherintravenously via the tail vein or orally using a pharyngeal tube.

b.2) Arterial Thrombosis Model (Rat)

Male fasting rats (strain: HSD CPB: WU) were anesthetized as describedabove. On average, the rats had a weight of about 200 g. The leftcarotid artery was exposed (about 2 cm). The formation of an arterialthrombus was induced by mechanical injury to the blood vessel inaccordance with the method described by K. Meng et al.,Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To thisend, the exposed carotid artery was clamped from the blood flow, cooledto −12° C. in a metal trough for 2 minutes and, to standardize the sizeof the thrombi, simultaneously compressed using a weight of 200 g. Theblood flow was then additionally reduced by a clip which was placedaround the carotid artery distally from the injured section of thevessel. The proximal clamp was removed, and the wound was closed andre-opened after 4 hours to remove the injured section of the vessel. Thesection of the vessel was opened longitudinally and the thrombus wasremoved from the injured section of the vessel. The moist weight of thethrombi was determined immediately. The test substances wereadministered to the animals while awake at the beginning of theexperiment, either intravenously via the tail vein or orally using apharyngeal tube.

b.3) Venous Thrombosis Model (Rat)

Male fasting rats (strain: HSD CPB: WU) were anesthetized as describedabove. On average, the rats had a weight of about 200 g. The leftjugular vein was exposed (about 2 cm). The formation of a venousthrombus was induced by mechanical injury to the blood vessel inaccordance with the method described by K. Meng et al.,Naunyn-Schmiedeberg's Arch. Pharmacol. (1977), 301, 115-119. To thisend, the jugular vein was clamped from the blood flow, cooled to −12° C.in a metal trough for 2 minutes and, to standardize the size of thethrombi, simultaneously compressed using a weight of 200 g. The bloodflow was re-opened and the wound was closed. After 4 hours, the woundwas re-opened to remove the thrombi from the injured sections of thevessel. The moist weight of the thrombi was determined immediately. Thetest substances were administered to the animals while awake at thebeginning of the experiment, either intravenously via the tail vein ororally using a pharyngeal tube.

B PREPARATION EXAMPLES HPLC Parameters

[1] Column: Kromasil C18 60*2, L-R temperature: 30° C., flow rate=0.75mlmin⁻¹, mobile phase: A=0.01 M H₃PO₄, B=CH₃CN, gradient: ->0.5 min 90%A ->4.5 min 10% A ->6.5 min 10% A.[2] Column: Kromasil C18 60*2, L-R temperature: 30° C., flow rate=0.75mlmin⁻¹, mobile phase: A=0.005 M HClO₄, B=CH₃CN, gradient: ->0.5 min 98%A ->4.5 min 10% A ->6.5 min 10% A.[3] Column: Symmetry C18 2.1×150 mm, column oven: 50° C., flow rate=0.6mlmin⁻¹, mobile phase: A=0.6 g 30% strength HCl/1 water, B=CH₃CN,gradient: 0.0 min 90% A ->4.0 min 10% A ->9 min 10% A.

[4] MHZ-2P, Instrument Micromass Platform LCZ

Column Symmetry C18, 50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flowrate=0.5 mlmin⁺¹, mobile phase A=CH₃CN+0.1% formic acid, mobile phaseB=water+0.1% formic acid, gradient: 0.0 min 10% A ->4 min 90% A ->6 min90% A.

Starting Materials Example I 4-(4-Morpholin-3-onyl)aniline

I-a 4-(4-Morpholin-3-onyl)nitrobenzene

The preparation of morpholin-3-one is described in U.S. Pat. No.5,349,045.

Over a period of 2 hours, sodium hydride (88 g, 2.2 mol, 60% inparaffin) is added a little at a time to a solution of morpholin-3-one(202 g, 2 mol) in N-methylpyrrolidone (2 l). After the evolution ofhydrogen has ceased, 4-fluoronitrobenzene (282 g, 2 mol) is addeddropwise with cooling over a period of one hour, and the reactionmixture is stirred overnight. At 12 mbar and 76° C., 1.7 l of the volumeof the liquid is then distilled off, the residue is poured into water (2l) and this mixture is extracted twice with ethyl acetate (in each case1 l). The combined organic phases are washed with water, dried oversodium sulfate, filtered and concentrated under reduced pressure.Purification is carried out by chromatography (on silica gel,hexane/ethyl acetate 1:1) and subsequent crystallization from ethylacetate. Yield: 78 g (colorless to brownish solid), 17.6% of theory.

¹H NMR (300 MHz, CDCl₃): 3.86 (m, 2H, CH₂CH₂), 4.08 (m, 2H, CH₂CH₂),4.49 (s, 2H, CH₂CO), 7.61 (d, 2H, ³J=8.95 Hz, CHCH), 8.28 (d, 2H,³J=8.95 Hz, CHCH);

MS (r.I. %)=222 (74, M^(+.)), 193 (100), 164 (28), 150 (21), 136 (61),117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50 (25).

I-b 4-(4-Morpholin-3-onyl)aniline

In an autoclave, 4-(4-morpholin-3-onyl)nitrobenzene (63 g, 0.275 mol) isdissolved in tetrahydrofuran (200 ml), Pd/C (3.1 g, 5%) is added and themixture is hydrogenated at 70° C. and a hydrogen pressure of 50 bar for8 hours. The catalyst is filtered off and the solvent is then distilledoff under reduced pressure and the product is purified bycrystallization from ethyl acetate. Yield: 20 g (colorless to bluishsolid), 37.6% of theory. Alternatively, purification can also be carriedout by chromatography (on silica gel, hexane/ethyl acetate mixture).

¹H NMR (300 MHz, CDCl₃): 3.67 (m, 2H, CH₂CH₂), 3.99 (m, 2H, CH₂CH₂),4.27 (s, 2H, CH₂CO), 6.68 (d, 2H, ³J=8.71 Hz, CHCH), 7.03 (d, 2H,³J=8.71 Hz, CHCH);

MS (r.I. %)=192 (100, M^(+.)), 163 (48), 133 (26), 119 (76), 106 (49),92 (38), 67 (27), 65 (45), 52 (22), 28 (22).

Example II4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-3-morpholinone

II-a2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione

A suspension of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A.Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water(9:1, 140 ml) is heated under reflux for 14 hours (the precipitatedissolves; after some time, another precipitate is formed). Theprecipitate (desired product) is filtered off, washed three times withdiethyl ether and dried. The combined mother liquors are concentratedunder reduced pressure and, after addition of a second portion of2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3-(2H)-dione (2.84 g, 14.0mmol), suspended in ethanol/water (9:1, 70 ml) and heated under refluxfor 13 hours (the precipitate dissolves; after some time, anotherprecipitate is formed). The precipitate (desired product) is filteredoff, washed three times with diethyl ether and dried. Total yield: 10.14g, 92% of theory.

MS (ESI): m/z (%)=418 ([M+Na]⁺, 84), 396 ([M+H]⁺, 93);

HPLC (method 2): rt=3.34 min.

II-b2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione

Under argon, N,N′-carbonyldiimidazole (2.94 g, 18.1 mmol) anddimethylaminopyridine (catalytic amount) are added at room temperatureto a suspension of the aminoalcohol (3.58 g, 9.05 mmol) intetrahydrofuran (90 mol). The reaction suspension is stirred at 60° C.for 12 hours (the precipitate dissolves; after some time, anotherprecipitate is formed), a second portion of N,N′-carbonyldiimidazole(2.94 g, 18.1 mmol) is added and the mixture is stirred at 60° C. foranother 12 hours. The precipitate (desired product) is filtered off,washed with tetrahydrofuran and dried. The filtrate is concentratedunder reduced pressure, and further product is purified by flashchromatography (dichloromethane/methanol mixtures). Total yield: 3.32 g,87% of theory.

MS (ESI): m/z (%)=422 ([M+H]⁺, 100);

HPLC (method 3): rt=3.37 min.

II-c4-{4[(5S)-5-Aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}-3-morpholinone

At room temperature, methylamine (40% in water, 10.2 ml, 0.142 mol) isadded dropwise to a suspension of the oxazolidinone (4.45 g, 10.6 mmol)in ethanol (102 ml). The reaction mixture is heated under reflux for onehour and concentrated under reduced pressure. The crude product is usedfor the next reaction without further purification.

MS (EST): m/z (%)=292 ([M+H]⁺, 100);

HPLC (method 2): rt=2.66 min.

Example III(5S)-5-(Aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one

III-a Benzyl 4-(2-oxo-1-pyrrolidinyl)phenylcarbamate

At −20° C., benzyl chloroformate (4.27 g, 25.03 mmol) is slowly addeddropwise to 1-(4-aminophenyl)pyrrolidin-2-one (4 g, 22.7 mmol) andN,N-dimethylaniline (3.6 ml, 28.4 mmol) in tetrahydrofuran (107 ml). Thereaction mixture is stirred at −20° C. for 30 min and then warmed toroom temperature. After addition of ethyl acetate (0.5 l), the organicphase is washed with saturated NaCl solution (0.5 l). The combinedorganic phase are dried (magnesium sulfate), filtered and concentratedunder reduced pressure. The residue is titrated with diethyl ether andfiltered off with suction. Yield: 5.2 g, 74% of theory, light-beigecrystals, melting point: 174° C.

III-b(5R)-5-(Hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one

Under argon, n-butyllithium (7.27 ml, 2.5 M solution in hexane) is, at−10° C., added dropwise to isoamyl alcohol (1.47 g, 16.66 mmol) intetrahydrofuran (200 ml) and further n-butyllithium is added until theadded indicator N-benzylidenebenzylamine changes its color. The reactionmixture is stirred at −10° C. for 10 minutes and cooled to −78° C., anda solution of benzyl 4-(2-oxo-1-pyrrolidinyl)phenylcarbamate (4.7 g,15.14 mmol) is added slowly. n-Butyllithium (2.5 M solution in hexane)is then added again, until the color of the indicator changes to pink.The reaction mixture is stirred at −78° C. for 10 minutes, R-glycidylbutyrate (2.62 g, 18.17 g) is added and the mixture is stirred at −78°C. for 30 minutes. The reaction mixture is warmed to room temperatureovernight, and water (200 ml) is added. The tetrahydrofuran fraction isremoved under reduced pressure. The aqueous residue is extracted withethyl acetate and the combined organic phases are dried with (magnesiumsulfate), filtered and concentrated under reduced pressure. The residueis titrated with diethyl ether (500 ml) and the precipitated crystalsare filtered off with suction. Yield: 3.76 g, 90% of theory.

Melting point: 148° C.,

R_(f)(SiO₂, toluene/ethyl acetate 1:1)=0.04, (starting material=0.3).

III-c(5S)-5-(Aminomethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one

At 0° C., methanesulfonyl chloride (1.79 g, 15.64 mmol) is added to asolution of(5R)-5-(hydroxymethyl)-3-[4-(2-oxo-1-pyrrolidinyl)phenyl]-1,3-oxazolidin-2-one(3.6 g, 13.0 mmol) and triethylamine (2.9 g, 28.7 mmol) indichloromethane (160 ml). The reaction mixture is stirred at 0° C. for1.5 hours and at room temperature for 3 hours and then washed withwater, and the aqueous phase is reextracted with dichloromethane. Thecombined organic phases are dried (magnesium sulfate), filtered andconcentrated under reduced pressure. The residue (1.67 g) is thendissolved in acetonitrile (70 ml), phthalimide potassium (2.62 g, 14.16mmol) is added and the mixture is stirred in a closed vessel in amicrowave oven at 180° C. for 45 min. Insoluble residue is removed fromthe mixture by filtration, the filtrate is evaporated under reducedpressure, the residue (1.9 g) is dissolved in methanol and hydrazinehydrate (0.47 g, 9.37 mmol) is added. The reaction mixture is heatedunder reflux for 2 hours and cooled, saturated sodium bicarbonatesolution is added and the mixture is extracted six times with methylenechloride (2 l in total). The combined organic phases are dried(magnesium sulfate), filtered and concentrated under reduced pressure.

The resulting product is used without further purification.

SYNTHESIS EXAMPLES Example 14-Chloro-N-({(5S)-2-oxo-4-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)benzamide

Under argon, 4-chlorobenzoyl chloride (72.1 mg, 0.41 mmol) is addeddropwise at room temperature to a solution of the amine II (80.0 mg,0.27 mmol) in pyridine (2 ml). The reaction mixture is stirred at roomtemperature for 2 hours and then diluted with pyridine (4 ml),aminomethylpolystyrene resin (2.5 eq.) is added and the mixture isshaken at room temperature for 1.5 hours. The resin is filtered andwashed repeatedly with dichloromethane/methanol (5:1). The combinedfiltrates are concentrated under reduced pressure. The desired productis purified by flash chromatography (dichloromethane/methanol mixtures).Yield: 105.1 mg, 89% of theory.

¹H NMR (DMSO-d⁶, 200 MHz): 8.90 (t, 1H), 7.86 (d, 2H), 7.60-7.50 (m,4H), 7.40 (d, 2H), 4.92-4.82 (m, 1H), 4.24-4.15 (m, 1H), 4.19 (s, 2H),4.00-3.93 (m, 2H), 3.93-3.85 (dd, 1H), 3.75-3.68 (m, 2H), 3.68-3.60 (m,2H);

MS (DCI, NH₃): m/z (%)=447 ([M+NH₄]⁺, 100);

HPLC (method 2): rt=3.76 min.

The following compounds were prepared analogously:

Ex- HPLC ample method: num- retention ber Structure Mass time 2

MS (ESI): m/z (%) = 414 ([M + H]⁺, 100) Method 4: 3.44 min 3

MS (ESI): m/z (%) = 458/460 ([M + H]⁺, 100) Method 4: 3.53 min 4

MS (ESI): m/z (%) = 414 ([M + H]⁺, 100) Method 2: 3.57 min 5

MS (ESI): m/z (%) = 386 ([M + H]⁺, 100) Method 2: 3.24 min

Example 65-Bromo-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-furamide

Under argon, N-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride(79.0 mg, 0.41 mmol) and dropwise, N,N-diisopropylethylamine (120 μl,0.69 mmol) are added at room temperature to a solution of the amine II(100.0 mg, 0.34 mmol), 5-bromo-2-furancarboxylic acid (78.7 mg, 0.41mmol) and 1-hydroxy-1H-benzotriazole (55.7 mg, 0.41 mmol) indimethylformamide (3.4 ml). The reaction mixture was stirred at roomtemperature for 16 hours and concentrated under reduced pressure. Thedesired product is purified by flash chromatography(dichloromethane/methanol mixtures). Yield: 79.6 mg, 50% of theory.

¹H NMR (DMSO-d⁶, 200 MHz): 8.79 (t, 1H), 7.56 (d, 2H), 7.41 (m, 4H),7.19 (d, 1H), 6.77 (d, 1H) 4.88-4.77 (m, 1H), 4.19 (s, 2H), 4.18 (dd,1H), 4.00-3.93 (m, 2H), 3.90-3.82 (dd, 1H), 3.75-3.67 (m, 2H), 3.62-3.53(m, 2H);

MS (ESI): m/z (%)=464 ([M+H]⁺, 100);

HPLC (method 1): rt=3.31 min.

The following compounds were prepared analogously:

Ex- HPLC ample method: num- retention ber Structure Mass time 7

MS (ESI): m/z (%) = 448 ([M + H]⁺, 100) Method 4: 3.18 min 8

MS (ESI): m/z (%) = 431 ([M + H]⁺, 100) Method 2: 3.46 min 9

MS (ESI): m/z (%) = 385 ([M + H]⁺, 100) Method2: 2.57 min 10

MS (ESI): m/z (%) = 404 ([M + H]⁺, 100) Method 2: 3.40 min 11

MS (DCI, NH₃): m/z (%) = 447 ([M + NH₄]⁺, 100) Method 2: 3.79 min

1. A compound of the formula (I)

in which R¹ represents (C₆-C₁₄)-aryl, 5- to 10-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S or 5- to 10-membered heterocyclyl having up to three heteroatoms from the group consisting of N, O and S, where the rings may be mono- to trisubstituted, independently of one another, by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, oxo, carboxyl or cyano, R² represents a radical —C(O)NR⁸R⁹, —N(R¹⁰)C(O)R¹¹ or

where R⁸ represents hydrogen, (C₁-C₆)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, (C₆-C₁₄)-aryl which for its part may be substituted by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C₃-C₇)-cycloalkyl, and R⁹ represents (C₁-C₆)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, (C₆-C₁₄)-aryl which for its part may be substituted by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C₃-C₇)-cycloalkyl, or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, R¹⁰ and R¹¹, independently of one another, represent (C₁-C₆)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, (C₆-C₁₄)-aryl which for its part may be substituted by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C₃-C₇)-cycloalkyl, or R¹⁰ and R¹¹ together with the N—C(O) group to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, x represents 0 or 1, R¹² and R¹³ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S and which may be up to disubstituted, independently of one another, by amino, hydroxyl, halogen, trifluoromethyl, cyano, oxo, mono- or di-(C₁-C₄)-alkylamino, (C₁-C₄)-alkoxy, carboxamido, (C₁-C₄)-alkylcarbonyl or (C₃-C₅)-cycloalkylcarbonyl, R³, R⁴, R⁵ and R⁶, independently of one another, represent hydrogen, halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, mono- or di-(C₁-C₆)-alkylaminocarbonyl, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkanoyl, (C₁-C₆)-alkanoylamino, trifluoromethyl, carbamoyl, nitro or cyano, and R⁷ represents hydrogen or (C₁-C₆)-alkyl, and its salts, hydrates, hydrates of the salts and solvates, but excluding compounds of the general formula (I) in which the radical R¹ is an optionally substituted thiophene radical.
 2. A compound of the formula (I) as claimed in claim 1, in which R¹ represents (C₆-C₁₄)-aryl, 5- to 10-membered heteroaryl having one nitrogen or oxygen atom as heteroatom and optionally up to two further heteroatoms from the group consisting of N, O and S or 5- to 10-membered heterocyclyl having up to three heteroatoms from the group consisting of N, O and S, where the rings may be mono- to trisubstituted, independently of one another, by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, oxo, carboxyl or cyano, R² represents a radical —C(O)NR⁸R⁹, —N(R¹⁰)C(O)R¹¹ or

where R⁸ represents hydrogen, (C₁-C₆)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, (C₆-C₁₄)-aryl which for its part may be substituted by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C₃-C₇)-cycloalkyl, and R⁹ represents (C₁-C₆)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, (C₆-C₁₄)-aryl which for its part may be substituted by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C₃-C₇)-cycloalkyl, or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, R¹⁰ and R¹¹, independently of one another, represent (C₁-C₆)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, (C₆-C₁₄)-aryl which for its part may be substituted by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)-alkanoyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, carboxyl or cyano, or (C₃-C₇)-cycloalkyl, or R¹⁰ and R¹¹ together with the N—C(O) group to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, x represents 0 or 1, R¹² and R¹³ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S and which may be up to disubstituted, independently of one another, by amino, hydroxyl, halogen, trifluoromethyl, cyano, oxo, mono- or di-(C₁-C₄)-alkylamino, (C₁-C₄)-alkoxy, carboxamido, (C₁-C₄)-alkylcarbonyl or (C₃-C₅)-cycloalkylcarbonyl, R³, R⁴, R⁵ and R⁶, independently of one another, represent hydrogen, halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, mono- or di-(C₁-C₆)-alkylaminocarbonyl, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkanoyl, (C₁-C₆)-alkanoylamino, trifluoromethyl, carbamoyl, nitro or cyano, and R⁷ represents hydrogen or (C₁-C₆)-alkyl, and its salts, hydrates, hydrates of the salts and solvates.
 3. A compound of the formula (I) as claimed in claim 1, in which R¹ represents phenyl, naphthyl, 5- to 8-membered heteroaryl having one nitrogen or oxygen atom as heteroatom and optionally up to two further heteroatoms from the group consisting of N, O and S or 5- to 8-membered heterocyclyl having up to three heteroatoms from the group consisting of N, O and S, where the rings may be mono- to trisubstituted, independently of one another, by halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, cyano, trifluoromethyl, trifluoromethoxy or trifluoromethylthio, R² represents a radical —C(O)NR⁸R⁹, —N(R¹⁰)C(O)R¹¹ or,

where R⁸ represents hydrogen, (C₁-C₄)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₄)-alkylamino, hydroxyl, oxo, (C₁-C₄)-alkoxy, trifluoromethyl or cyano or (C₃-C₇)-cycloalkyl, and R⁹ represents (C₁-C₄)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₄)-alkylamino, hydroxyl, oxo, (C₁-C₄)-alkoxy, trifluoromethyl or cyano, or (C₃-C₇)-cycloalkyl, or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, R¹⁰ and R¹¹, independently of one another, represent (C₁-C₆)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, or (C₃-C₇)-cycloalkyl, or R¹⁰ and R¹¹ together with the N—C(O) group to which they are attached form a 4- to 7-membered heterocycle which may contain up to two further heteroatoms from the group consisting of N, O and S and which may furthermore be mono- to trisubstituted, independently of one another, by halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, x represents 0 or 1, R¹² and R¹³ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S and which may be monosubstituted by amino, hydroxyl, halogen, trifluoromethyl, cyano, oxo, mono- or di-(C₁-C₄)-alkylamino, (C₁-C₄)-alkoxy, carboxamido, (C₁-C₄)-alkylcarbonyl or (C₃-C₅)-cycloalkylcarbonyl, R³ and R⁶, independently of one another, represent hydrogen, halogen, (C₁-C₆)-alkyl, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkanoylamino, cyano, trifluoromethyl or nitro, R⁴ and R⁵ represent hydrogen, and R⁷ represents hydrogen or (C₁-C₄)-alkyl, and its salts, hydrates, hydrates of the salts and solvates.
 4. A compound of the formula (I) as claimed in claim 1, in which R¹ represents phenyl, furyl, dihydrothienyl, thiazolyl, pyrrolyl or pyridyl, where the rings may be mono- to trisubstituted, independently of one another, by fluorine, chlorine, bromine, (C₁-C₄)-alkyl, trifluoromethyl, trifluoromethoxy or trifluoromethylthio, R² represents a radical —C(O)NR⁸R⁹, —N(R¹⁰)C(O)R¹¹ or

where R⁸ and R⁹, independently of one another, represent (C₁-C₄)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₄)-alkylamino, hydroxyl, oxo, (C₁-C₄)-alkoxy, trifluoromethyl or cyano, or (C₃-C₇)-cycloalkyl, or R⁸ and R⁹ together with the nitrogen atom to which they are attached represent morpholinyl, pyrrolidinyl, thiomorpholinyl or piperidinyl, where the rings may be mono- or disubstituted by (C₁-C₄)-alkyl and/or oxo, R¹⁰ and R¹¹, independently of one another, represent (C₁-C₆)-alkyl which for its part may be substituted by halogen, amino, mono- or di-(C₁-C₆)-alkylamino, hydroxyl, oxo, (C₁-C₆)-alkoxy, trifluoromethyl or cyano, or (C₃-C₇)-cycloalkyl, or R¹⁰ and R¹¹ together with the N—C(O) group to which they are attached represent morpholinonyl, pyrrolidinonyl, thiomorpholinonyl or piperidinonyl, where the rings may be mono- or disubstituted by (C₁-C₄)-alkyl, x represents 0 or 1, R¹² and R¹³ together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocycle which may contain a further oxygen atom in the ring and which may be monosubstituted by amino or hydroxyl, R³ represents hydrogen, fluorine, chlorine, bromine, (C₁-C₄)-alkyl, amino, mono- or di-(C₁-C₃)-alkylamino, cyano or nitro, R⁴, R⁵ and R⁶ represent hydrogen, and R⁷ represents hydrogen, and its salts, hydrates, hydrates of the salts and solvates.
 5. A process for preparing compounds of the formula (I) as claimed in claim 1, characterized in that compounds of the formula (II)

in which R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above are reacted with carboxylic acids of the formula (III)

in which R¹ is as defined above, or else with the corresponding carbonyl halides or else with the corresponding symmetric or mixed carboxylic anhydrides of the carboxylic acids of the formula (III) defined above.
 6. A compound of the formula (I) as claimed in claim 1 for the prevention and/or treatment of disorders.
 7. A medicament comprising at least one compound of the formula (I) as claimed in claim 1 and at least one further auxiliary.
 8. The use of compounds of the formula (I) for preparing a medicament for the prevention and/or treatment of thromboembolic disorders, in particular myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, cerebro vascular accident, transitory ischemic attacks, peripheral occlusive diseases, pulmonary embolisms or deep vein thromboses.
 9. The use of compounds of the formula (I) as claimed in claim 1 for preparing a medicament for the prevention and/or treatment of disseminated intravasal coagulation (DIC).
 10. The use of compounds of the formula (I) as claimed in claim 1 for preparing a medicament for the prevention and/or treatment of disorders such as atherosclerosis; arthritis; Alzheimer's disease or cancer.
 11. A process for preventing the coagulation of blood in vitro, in particular in banked blood or biological samples containing factor Xa, characterized in that compounds of the general formula (I) as claimed in claim 1 are added. 